It is now found that Compounds from among known and selected novel arylmethylenyl derivatives of thiazolidinones, oxazolidinones or imidazolidinones have activity useful for treating allergies or inflammation.
Thus, the present invention is for selected novel compounds, as well as, pharmaceutical compositions and methods of use for known compounds and the selected novel compounds of the formula (I) ##STR2## and pharmaceutically acceptable salts thereof; wherein Ar is (i) phenyl unsubstituted, (ii) phenyl substituted by from one to three of lower alkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl, NR.sub.10 R.sub.11 wherein R.sub.10 and R.sub.11 are independently hydrogen or lower alkyl, NO.sub.2, mercapto, or lower alkylthio, (iii) naphthyl; (iv) benzofuranyl, [v) benzothiophenyl, (vi) 2- or 3-thienyl, (vii) 2- or 3-indolyl, (viii) 2- or 3-furanyl, or (ix) 2-, 3-, or 4-pyridyl;
Y and Y.sub.1 is oxygen or sulfur;
X is sulfur, oxygen, NH or NCH.sub.3 and
X.sub.1 is NH or NC.sub.3 with the proviso that when Ar is substituted phenyl, the substituents are either not 3,5-di(isopropyl)-4-hydroxy or if X.sub.1 =NH, X=S, Y=S not 3,5-di(t-butyl) together with 4-hydroxy.
Japanese Application No. 84-133826 as found in Derwent Abstracts No. 87-076379/11 discloses new 3,5-diisopropylbenzylidene-2,4-imidazolidinone and the analogous thiazoles with antiallergic and tyrosine kinase inhibiting activity as well as other heterocyclic containing compounds. EP No. 211,670A as described in Derwent 87-051809/08 describes compounds excluded by the proviso above having a 3,5-diisobutylbenzyledene substituent useful for treating inflammation, ischaemia induced cell damage and arthritis. Thus, known heterocyclic compounds are not as closely related as these named here and are excluded from the present invention.
A French Patent No. 2,169,334, C. H. Boehringer Sohn, Oct. 12, 1973 describes a series of N-substituted oxazoles as antiarthritics. antirheumatics, and immunosuppressants having the formula ##STR3## which are not included in the present invention.
Copending application PD-3518 is for novel compounds having a 3,5-di-tertiarybutyl-4-hydroxyphenyl moiety so its disclosure relating to references in the Background of the Invention is incorporated herein by reference.
The compounds of the formula I have a hitherto unknown pharmaceutical activity useful for treating allergic or inflammatory conditions or diseases. The invention compounds are now also found to have activity as inhibitors of 5-lipoxygenase and/or cyclooxygenase providing treatment of conditions advantageously affected by such inhibition including inflammation, arthritis, pain, pyrrhia, and the like. Thus, the present invention is also a pharmaceutical composition for diseases or conditions advantageously affected by activity inhibiting singly or together 5-lipoxygenase and cyclooxygenase or method of use therefor. Therefore, the present invention is particularly a pharmaceutical composition for the treatment of allergy or inflammation which comprises an antiallergy or antiinflammatory effective amount of a compound of the formula I together with a pharmaceutically acceptable carrier. Further, the present invention is a method for treating allergies or inflammation in subject suffering therefrom which comprises administering a compound of the formula I in unit dosage form.
The present invention is also the novel selected compounds of the formula I noted hereinafter having activity heretofore unknown for analogous compounds.
Among the known compounds for the compositions or methods of use of the present invention the following are referenced for compounds listed for the Examples of the invention:
______________________________________ Example No. Reference ______________________________________ 1 J. Chem. Soc., pp. 958-65 (1946) 2 J. Org. Chem., 26, p. 1326 (1961) 3 Chem. Ber., pp. 459-69 (1941) 4 J. Chem. Soc., pp. 3547-52 (1950) 5 J.C.S., p. 1165 (1954) 6 J. Org. Chem., p. 1326 (1961) 7 U.S. Pat. No. 3,843,797/JACS, p. 2357 (1951) 8 C.A. 89: 100767m, JACS, p. 2357 (1951) 9 Tet., p. 2781 (1969) 10 Canadian J. Chem., p. 2089 (1959) 12 Ger. Pat. DE 3,433,475/C.A. 103, 928404 17 J.O.C., p. 32 (1956) 18 Tet., p. 2781 (1969) 19 Tet., p. 2781 (1969) 20 Tet., p. 2781 (1969) 21 J. Ind. Chem. Soc., p. 77 (1984) 22 J. Ind. Chem. Soc., p. 77 (1984) 26 See Example 8 above 28 Int. J. Sulf. Chem. Part A, p. 261 (1972) 29 C.A. 76 (5), 25152h 30 C.A. 79 (25), 143522p 32 C.A. 76 (5), 25152h 34 C.A. 79 (25), 143522p 36 Biol. Mem. 9, 200 (1984) 38 Zh. Or. Khim, p. 212 (1983) 40 J.C.S. (1), p. 385 (1984) 41 C.A. 89: 100767n 42 Chem. Phar. Bull., p. 1619 (1986) 43 Int. J. Sulf. Chem. Part A, p. 261 (1972) 44 J. Pharm. Soc. Jap., p. 154 (1956) 45 Ger. Pat. DE 3,433,475 48 J.C.S., p. 3547 (1950) 49 C.A. 7, 9543a 50 C.A. 47, 9543a 68 C.A. 71 (17), 81253a 69 Zh. Ob. Khm 26, p. 3092 (1956) 71 Ukrain Khim Zh. 16, p. 545 (1950) 83 Chem. Pharm. Bull., p. 1619 (1986) 86 Am. Chem. J., p. 368 (1911) 87 JACS, p. 1606 (1913) 90 JACS, p. 1606 (1913) 91 Monats, p. 352 (1961) 92 Chem. Pharm. Bull., p. 1619 (1986) 96 Roecz, Chem., p. 1381 (1984) 103 U.S. Pat. No. 3,017,270 104 Egypt J. Chem., 26, 301 (1983) 105 French Pat. No 1,604,530 ______________________________________
The selected novel compound of the present invention are found in Examples 11, 13-16, 51-53, 55-63, 64, 70, 72-79, 80, 82, 88, 97, and 99-101, 106-111.
Accordingly, the present invention is
(a) a selected novel compound as in the noted examples heretofor or a salt thereof;
(b) a method for preparing a novel selected compound or a pharmacologically acceptable salt thereof;
(c) a pharmaceutical composition comprising a compound of formula (I) or a physiologically acceptable salt thereof and a pharmaceutically acceptable carrier therefor;
(d) a method for preparing such compositions;
(e) a method for the inhibition of histamine by use of a nontoxic, effective, inhibitory amount of a compound of formula I or a physiologically acceptable salt thereof;
(f) a method for the prophylaxis or treatment of disease or condition in a mammal, including man, comprising the administration to said mammal of a nontoxic, therapeutically or prophylactically effective amount of a compound of formula I or a physiologically acceptable salt thereof;
(g) a method for the prophylaxis or treatment of any individual condition described herein, in a mammal, including man, comprising the administration to said mammal of a nontoxic therapeutically or prophylactically effective amount of a compound of formula I or a physiologically acceptable salt thereof;
(h) a method for the prophylaxis or treatment of allergy or inflammatory condition in a mammal, including man, comprising administration to said mammal of a nontoxic, effective, antiallergic or antiinflammatory amount of a compound of formula I or a physiologically acceptable salt thereof;
(i) a novel compound as set out in the examples noted heretofor or a physiologically acceptable salt thereof for use in medicine, especially as defined in (f)-(h) above;
(j) use of a compound of formula I or a physiologically acceptable salt thereof in the manufacture of medical therapeutic agents, particularly those for use as defined in (f)-(h) above; and
(k) any novel feature described herein.